This HIT-IT proposal addresses the hypothesis that an agent designed to bind to HIV-1 envelope spike glycoprotein gp120 and insert into the viral membrane simultaneously can deliver a membrane-directed force to the spike, thereby causing it to porate its own membrane, resulting in outflow of viral contents and deactivation of the virus. This hypothesis is based on the vision that (i) the mature HIV virion is likely osmotically stressed, and (ii) one role of the viral spike glycoprotein gp41 is to destabilize the viral membrane. In this work, we will design, test and optimize chimerae with gp120-binding and membrane-insertion domains. The project relies on a highly interconnected simulation/experimentation approach. If successful, our results will form the basis upon which a completely new class of virucidal agents can be developed. We propose to develop virucides against HIV-1 based upon a novel interpretation of the viral life cycle. These molecules will be designed to hijack essential viral properties, normally used to infect cells, in such a way as to "trick" the virus into self-destructing in the absence of a target cell. If successful, this work will form the basis for the development of potent, cheap and easy-to-manufacture microbicides for preventing the spread of AIDS.